Cyclic nucleotide phosphodiesterases (CN-PDE) show specificity for purine cyclic nucleotide substrates and hydrolyze cyclic AMP (cAMP) and cyclic GMP (cGMP; Thompson, W. J. (1991) Pharmac. Ther. 51:13-33). CN-PDEs regulate the steady-state levels of cAMP and cGMP and modulate both the amplitude and duration of cyclic nucleotide signals. cAMP and cGMP, in turn, are important "second messenger" molecules in signal transduction, the general process by which cells respond to extracellular signals (hormones, neurotransrnitters, growth and differentiation factors, etc.). Signal transduction regulates all types of cell functions including cell proliferation, differentiation, and gene transcription.
At least seven different but homologous gene families of CN-PDEs are currently known to exist in mammalian tissues. Most families contain distinct genes, many of which are expressed in different tissues as functionally unique alternative splice variants (Beavo, J. A. (1995) Physiological Reviews 75:725-748.) The seven families of CN-PDEs are categorized in terms of tissue localization, CN specificity and physiological function. Known physiological functions of CN-PDEs include modulation of neural synaptic transmission, cardiac muscle contractility, blood pressure regulation, platelet aggregation, odorant transduction, and phototransduction in the eye (Beavo, supra.)
Members of the type 6 family of CN-PDEs are associated with retinal phototransduction and are the most well understood CN-PDEs in terms of biochemical function (Stryer, L. (1991) J. Biol. Chem. 266:10711-14). In phototransduction, light impinging on a photoreceptor cell triggers a nerve signal by activating a cascade of biochemical events leading to the hydrolysis of cGMP by CN-PDE6. The decrease in cGMP leads to the closing of a cGMP-gated cation channel in the photoreceptor membrane generating the nerve signal. Recovery of the dark state of the cell is mediated by deactivation of CN-PDE6, activation of guanylcyclase, and restoration of cGMP levels. CN-PDE6 is a tetrameric protein composed of two catalytic subunits (.alpha. and .beta.) and two inhibitory subunits (.gamma.). Dissociation of the inhibitory .gamma. subunits from the enzyme complex is induced by a membrane associated protein called transducin and activates the enzyme. Reassociation of the inhibitory subunits with the catalytic subunits is induced by a second protein, recoverin, which deactivates the enzyme. CN-PDE6 is associated primarily with the disk membrane of the outer rod segments of retinal cells. However, a soluble form of the enzyme has been found that contains a fifth subunit (.delta.; Florio, S. K. et al. (1996) J. Biol. Chem. 271:24036-47). The 17 kDa .delta. subunit is found only in association with the soluble form of CN-PDE6 and has been shown to solubilize membrane-bound CN-PDE6 by binding to the C-terminal portion of the enzyme and releasing it from the rod membrane. This action is believed to reduce the ability of membrane-bound transducin to activate CN-PDE6 and provides another level of enzyme regulation. Northern analysis indicates that the .delta. subunit is highly expressed in retinal tissues and is found in various non-retinal tissues as well (Florio, supra). Thus the .delta. subunit may serve a regulatory function with CN-PDEs in both retinal and non-retinal tissues.
Defects in CN-PDEs are associated with retinal disease, diabetes, cardiac disease, cancer, and inflammatory diseases. CN-PDE inhibitors have been used to treat thrombosis, hypertension, inflammation, and bronchial asthma. In addition, pre-clinical studies have further indicated the potential for CN-PDE inhibitors to treat cancer, HIV infections (AIDS), and multiple sclerosis (Angel, J. B. et al. (1995) AIDS 9:1137-44; Sommer, N. et al. (1995) Nat. Med. 1:244-48; and Bang, Y. J. et al. (1994) Proc. Natl. Acad. Sci. 91:5330-34).
The discovery of a new human phosphodiesterase regulatory subunit and the polynucleotides encoding it satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in the treatment or prevention of cancer, immune disorders, and neurological disorders.